Activation, proliferation and differentiation of a distinct phenotype of hepatic cells, called oval cells, are observed after severe hepatic injuries, especially when proliferation of hepatocytes is inhibited. Under those conditions, oval cells can act as bipotential progenitors of the two types of epithelial cells of the liver, the hepatocytes and bileductular cells. Oval cells have been usually thought to be the progeny of a hepatic stem cell, native to the liver. However, we have obtained clear evidence that in the rat, hepatic oval cells, or at the least a fraction of them, can derive from a precursor cell of bone marrow origin. The goals of this project are therefore to determine how bone marrow stem cell emigration to the liver is regulated, what local hepatic environment promotes engraftment of bone marrow cells as an oval cell population, and what bone marrow-derived cell population can best act as a progenitor of hepatic oval cells. Towards achievement of these goals, we will perform a series of studies aimed at increasing the efficiency of bone marrow cell recruitment to test the hypothesis that the type of injury (periportal vs. pericentral) and chemokine (CC vs. CXC) response being invoked determines the efficiency with which bone-marrow stem/precursor cells engraft in an injured liver in both rat and mouse models (Specific Aim I); to determine whether the homing chemokine SDF- 1 and its receptor CXCR4 play a role in directing the bone marrow precursor cell to the liver (Specific Aim Il); and to establish whether the CD-34+ or CD-34- sub-population of bone marrow cells contains the oval cell progenitor and produces the higher percentage of bone marrow derived hepatocytes (SpecificAim III). It is anticipated that performance of the proposed studies will yield new and significant data about the overall mechanisms for recruitment of hepatic oval cells, and the basic phenotype and properties of their bone marrow precursor. These data will be critical for developing novel therapeutic strategies for the treatment of liver disease.